Roles of G-protein-coupled receptor signaling in cancer biology and gene transcription
Introduction
G-protein-coupled receptors (GPCRs) are crucial intermediates in the transmission of extracellular information into intracellular responses. Activated GPCRs typically control cellular physiology by releasing the signaling potential of inactive heterotrimeric G-proteins [1]. These inactive heterotrimers consist of a guanine diphosphate-bound Gα subunit, which maintains a high affinity for a Gβγ functional monomer. Upon activation by a cognate ligand or signal, a GPCR catalyzes the exchange of GTP for GDP on the Gα subunit, resulting in a decreased affinity of Gα for Gβγ. This alteration causes dissociation of the subunits [1] or rearrangement of the heterotrimer [2], allowing Gα and Gβγ to interact with and to modulate the activities of a diverse and growing repertoire of effector molecules [1, 3].
Aberrant functioning of GPCR pathways leads to several important human diseases, including endocrine and vision disorders [4]. Accordingly, GPCR-mediated signaling holds a position of prominence in clinical pharmacology [5, 6]. In cancer therapy, however, GPCR-targeted drugs are used only peripherally. For instance, GPCR-targeting analgesics, such as the opioid receptor agonist oxycodone (Oxycontin), are used in pain management. Here, we review recent advances that have revealed fundamental links between GPCR-mediated pathways and cancer biology and gene transcription. Thus, future chemotherapy development might be poised to take advantage of the vast knowledge of GPCRs and their ligands.
This review highlights recent data linking G-protein-coupled receptors and their intracellular messaging partners, heterotrimeric G-proteins, to the biology of cancer. We emphasize the burgeoning field of nuclear heterotrimeric G-proteins and discuss potential implications for a direct regulation of gene transcription by heterotrimeric G-proteins.
Section snippets
GPCRs in cancer biology
Although GPCRs and heterotrimeric G-proteins have not garnered the notoriety of p53, Ras, PTEN (Phosphatase and tensin homologue deleted on chromosome ten) or other noteworthy oncogenes and tumor suppressors, a large body of evidence links aberrant G-protein signaling to cancer development and progression. For example, a recent examination of publicly available gene expression data identified a variety of types of GPCRs that are overexpressed in diverse types of cancer tissues [7]. Causal
Gα12/13 proteins in metastasis
The oncogenic potential of GPCRs is the result of a complex interplay among downstream heterotrimeric G-proteins. The transforming potential of various classes of Gα subunits have been discovered through overexpression of constitutively active mutants. Interestingly, Gα12/13 proteins seem to be the most potent oncogenes, because they comprise the only family for which overexpression of wild type proteins has been found to be transforming [9, 10]. Recent work has linked the enigmatic Gα12/13
G-proteins in the nucleus
Given that aberrant gene expression is a major factor in cancer, interactions between G-proteins and transcription are of fundamental importance. Indirect effects of G-protein signaling on gene transcription have been well established. For instance, both Gα- and Gβγ-dependent mechanisms are major modulators of MAPK signaling cascades [33], leading to phosphorylation and activation of transcription factors and other partner proteins [34]. Recent discoveries of several novel roles for G-proteins
Conclusions
GPCRs represent a rich source of validated drug targets in several therapeutic regiments [5, 6]. As more data linking these systems to the development and progression of cancer emerge, GPCRs and their associated factors will become increasingly attractive as targets for novel strategies targeting tumors and metastasis. Particularly exciting in this regard is the rapidly growing field linking G-proteins directly to normal and aberrant gene transcription.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We thank Dr Songhai Chen for critical reading of the manuscript. Unpublished work discussed in this review was supported by the National Institutes of Health (EY10291).
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